The present invention relates to a method of making a model equivalent to living tissue, such as a simulating image, phantom or reference material, which is required in maintenance, inspection, servicing, adjustment and appraisal of a system used for diagnosis by nuclear magnetic resonance (NMR) imaging and which is also required in analysis and study of the images obtained by the NMR diagnosis. More particularly, the present invention relates to a method of making a phantom for NMR diagnosis, the phantom being adapted for the inspection of the discrimination ability of the system, namely the ability of the system for detecting the difference in water contents, spin-lattice relaxation time and spin-spin relaxation time between different samples.
The method for the diagnosis of an internal site of a living body, for instance, to have an information concerning a certain lesion site or a condition of blood stream, is generally referred to as the NMR imaging method, the NMR tomographical diagnosis method, MRI (magnetic resonance imaging) method, the MMR (medical magnetic resonance) method, the MNI (multi-nuclear imaging) method, and the NMR-CT (computerized or computer assisted tomography) method. In such a method, a living body is placed in a static magnetic field and a radio-frequency wave having a high frequency corresponding to the resonance wave length is applied so that the atomic nuclei of hydrogen or proton in the living tissue are excited, and then the magnetic informations generated from the thus excited atomic nuclei are detected as the output signals to form an image by such output informations. Such an image includes the nuclear magnetic informations concerning the concentration of protons contained in the living tissue (which gives an information concerning the water content in the living tissue), those concerning the spin-lattice (longitudinal) relaxation time (T.sub.1) and those concerning the spin-spin (transverse) relaxation time (T.sub.2). By analyzing the image, the condition of the lesion site may be discriminated, and the distribution of blood stream velocity in the living tissue may be imaged. The NMR imaging method is expected as a novel tool for the early stage diagnosis of a variety of diseases, since it is superior over or overcoming the demerits of the known X-ray tomography, DSA (digital substraction angiography), PET or PE-CT (positron emission tomography) and US (ultrasonic method) for the reasons that any desired cross section of a living tissue can be imaged without trespassing internally of the living tissue, without being disturbed by the bones or air in the respiratory organs, and without any apprehension of exposure by a radioactive isotope or X-ray (In this connection, reference should be made to C. L. Partain et al., "Nuclear Magnetic Resonance Imaging" (1983), W. B. Sanders Co.). However, the conventional system used for the NMR diagnosis is inferior in operational stability when compared with the stabilities of the systems used for the X-ray-CT and PE-CT methods In practice of the NMR imaging, the system used therefor must always be paid with continuous care as to its maintenance, inspection, servicing, adjustment and appraisal of the performance characteristics.
In general, the device for reading out an information and the display device incorporated in the NMR system used for the chemical analysis are computerized, and it has been pointed out that "there is a grave tendency that exceedingly many chemists apt to accept the displayed data as accurate analytical results without taking what has been done in the system into account." In the NMR system for diagnosis, the control system, the manual for operations and the mode of imaging have not yet been standardized, often leading to difficulty in study and analysis of the image. Under such circumstances, certain erroneous diagnoses have been specifically pointed out and there is earnest demand for the search and establishment of a standard probe used for inspecting the operational condition of the system (E. L. Madsen, "Mag. Res. Imag.", 1, 135 (1982)).
The performance characteristics of NMR systems are significantly affected by the maintenance, control and adjustment operations. In addition, influences by magnetic materials, such as steel or iron used to construct a building in which the NMR system is housed, must be amended by the provision of a symmetrical coil. It is further necessary to adjust the frequency and to adjust the static magnetic field by amending or compensating the influences due to magnetic field established by radio frequency waves or plate-shape magnetic wave sources. However, significant difficulties are encountered in such adjustment or amendment operations. Furthermore, since the system cannot be assembled precisely in accordance with the theory and design thereof, similarly to general precise mechanical instruments, there is frequently pointed out the uneven orientation of the static magnetic field in the transverse direction, and it is hard to perfectly amend such uneven orientation of the magnetic field. Although it is convenient from the economical standpoint of view to lessen the magnetic field in order to improve the uniformity of the static magnetic field, it is meaningless to provide an NMR system for handling a small sample or test specimen when the system is to be used for the diagnosis of a human body. It should also be appreciated that a large scale magnet used for the diagnosis of a human body is accompanied with various imperfections which are not corrected or amended to give satisfactory data since any standard therefor has not yet been established at the present day (See D. J. Hoult, "Rev. Sci. Instrum.", 56 (1) 131 (1985) and R. T. Droege et al., "Radiology", 148, 763 (1983).).
In the meantime, the operation of the system also involves many problems which should be born in mind of the operator or the analyst. For example, the level of the radio frequency wave and the pulse interval should be properly selected, and the scanning speed should be pertinently set not to reduce the resolution power of the system, depending on the conditions of the disease. Furthermore, the NMR signals depend on the specific type of the system used, particularly on the intensity of the static magnetic field in the system, and the conversion factor between different systems cannot be determined monistically, as reported by I. Young, "Electronics & Power", 1984, March, 205. Moreover, even when the same system is used, the T.sub.1 and T.sub.2 (image signals) vary in response to the pulse interval (T.sub.r), the delay time (T.sub.d) and the echo time (T.sub.e). However, the photographing condition for imaging cannot be set monistically to a certain condition. In detail, the difference (i.e. the contrast between the image of normal tissue and that of diseased site) in the NMR signal induced by the change due to a morbid state is to be discriminated by the NMR diagnosis. However, since more than an hour is expended for individual imaging by calculation of the NMR signals (proton density .rho., T.sub.1 and T.sub.2) and since special value cannot always be expected by such individual imaging, it is a common practice to form an image including all of the above factors as prompt measure. In such a case, rather than taking the aforementioned three factors equally into account, endeavor is directed to the establishment of an image having clear contrast so as to have the maximum discrimination ability for discriminating the lesion site by imaging the respective factors through the non-uniformly weighed addition (while adopting the trial-and-error method) in response to the condition of disease, the personal difference and the conditions of the surrounding tissues around the lesion site (In this connection, reference should be made to G. Hansen et al., "Radiology", 136, 695 (1980) and I. E. Crooks, "I.E.E.E. Trans. Nucl. Sci.", NS-27, 1239 (1980)). For these reasons, unitary display of the NMR signals is sacrificed to result inevitably in devoid of interchangeability between the images to induce problems in analysis of the images, as reported by T. Araki et al., "Radiology", 150, 95 (1984).
In consideration of the aforementioned status quo of the NMR imaging technology, it is a natural demand for a reference or control specimen for the objective appraisal, judgement on the maintenance, control, adjustment, operational condition and performance condition and for the analysis of the displayed images. Examples of the materials proposed as those which may be used for the preparation of a reference specimen in the NMR imaging method, include tetramethylsilane, hexamethyldisiloxane, hexamethyldisilane, neopentane, DSS (sodium 2,2-dimethyl-2-silapentano-5-sulfonate) and sodium 2,3-tetradeuterium-3-trimethylsilylpropionate. Although these materials are conveniently used in the chemical analysis as the materials for preparing reference specimens used to measure the chemical shifts of the NMR informations, they are not suited for use as the material for the reference specimen used to provide basic informations or factors (proton density .rho., T.sub.1 and T.sub.2) in the NMR diagnosis, at all.
In some cases, poly(methyl methacrylate) and a low density polyethylene have been used in an NMR system for the adjustment purpose. However, the poly(methyl methacrylate) is used merely for the inspection of the peak width of the chemical shift during the chemical analysis, and the low density polyethylene is used only for the adjustment of the level of radio frequency wave. Neither materials have utility as the reference materials used for the adjustment operation when the system is used for obtaining NMR informations concerning a living body.
It has been proposed to use water, an aqueous solution of manganese sulfate, nickel chloride or copper sulfate or sulfuric acid, as the standard for inspection and adjustment of the system, since the NMR diagnosis is applied for the diagnosis of a substance (i.e. a living tissue) containing a large quantity of water. However, water is improper for a standard material used in the NMR analysis, since T.sub.1 and T.sub.2 of water are seriously affected by temperature and are also affected by dissolved oxygen. On the other hand, it is extremely difficult to prepare a solution simulating NMR informations of a living tissue (water content. T.sub.1 and T.sub.2) by the use of any of the aforementioned solutions.
There are known in the art a variety of solids or gels containing water and having structures resembling the living tissues, the examples being gelatin, agar, polyacrylamide, carrageenan, agarose, jam, boiled egg, KONNYAKU (devil's tongue), alginic acid gel and bean-curd. However, a material having a water content agreed with those of the internal organs of a living body (namely, having a water content of from about 70 to 85 wt %) and having the T.sub.1 and T.sub.2 values agreed with those of the internal organs of a living body has not yet been known (In this connection, reference should be made to O. Hechter et al., "Proc. Natl. Acad. Sci.", 46, 783 (1960); C. Sterling et al., "Makromol. Chem.", 116, 140 (1968); D. E. Woessner et al., "J. Colloid. Interface Sci.", 34, 283, 290 (1970); W. Derbyshire et al., "Disc. Farad. Soc.", 1974, 243; C. J. G. Bakkert et al., "Phys. Med. Biol.", 29, 1511 (1984); and R. M. Vre et al., "Mag. Res. Med.", 2, 176 (1985)). Although continuous attempts are made to improve the process for the preparation of these hydrogels so as to bring the NMR signals (.rho., T.sub.1 and T.sub.2) thereof close to those of living tissues by admixing some quantity of impurities, such attempts have not succeeded as will be described hereinbelow. For instance, even gelatin containing water considerably less than that of the living body has disadvantageously high T.sub.1 and T.sub.2 values. Although an approach for improving the properties of gelatin had been continued, such an approach produced no valuable fruit, since there appeared uneven gelation during the step of cross-linking and solidifying the gelatin. Anyway, it is not possible to bring the three factors, i.e. the water content (ranging within 70 to 85%), T.sub.1 and T.sub.2, close to those of the living tissues by the use of any gelatin composition. Although a polyacrylamide gel having a water content ranging from 70 to 85% may be prepared, such a gel has an exceedingly high T.sub.2 value and is apt to lose uniform structure during the cross-linking polymerization (gelation) step. Agar or agarose has an exceedingly high T.sub.1 value and a remarkedly low T.sub.2 value as compared with those of the living tissues.
Other known materials include bean-curd, carrageenan, alginic acid, boiled egg, poly(2-hydroxyethyl methacrylate) gel, Curdlan, carboxymethyl cellulose (CMC), acrylonitrile-starch graft gel (see E. B. Bagley et al., "Ind. Eng. Chem. Prod. Res. Dev.", 14 105 (1975)), xanthane gum, Locust Bean Gum, tragacanth gum, furcellaran, methyl cellulose, casein, albumin, fucoidin, triethanolamine alginate, tamarind gum, karaya gum, gatti gum and jam (such as pectin gel). However, properties of all of these known materials cannot be brought to be equivalent to the water content and T.sub.1 and T.sub.2 values of the living tissues.
KONNYAKU has an excessively high water content and considerably high T.sub.1 and T.sub.2 values Although poly(N-vinylpyrrolidone) has an adequate water content, it is too high in T.sub.1 and T.sub.2 values. Even if an adjusting agent, such as nickel, manganese, copper or graphite, is added to poly(N-vinylpyrrolidone), both of T.sub.1 and T.sub.2 values thereof cannot be brought to the values equivalent to those of living tissues.
A gel having an adequate water content (ranging within 70 to 85 wt %) may be prepared by exposing an aqueous solution of polyvinyl alcohol to gamma-ray. However, the T.sub.1 and T.sub.2 values of the thus prepared gel are lowered as the results of exposure to gamma-ray.
Because of the fact that any of the known materials (chemical substances) have many demerits, as described above, a fresh tissue of an animal has been used reluctantly as the control material in practice. However, such an animal-originated material is deteriorated significantly with the lapse of time even when stored in a cold place, as reported by R. V. Damadian, U. S. Pat. No. 3,789,832 (1974), and significant differences are found between the samples extracted from individual animals of the same species. Under such circumstances, it should be reasonable and well-grounded to accept the opinion, in which it has been repeatedly pointed out that it is necessary to find out a water-containing material (for phantom) which is not originated from a living body (in other words, a chemical substance) and repeatedly usable for a long time while having substantially equivalent NMR informations (.rho., T.sub.1 and T.sub.2) and being improved in shape-retaining property and satisfactory moldability.
For use as a phantom for NMR diagnosis proposed is a hydrogel having a high water content and prepared by casting an aqueous solution containing more than 8 wt % and not more than 50 wt % of polyvinyl alcohol having a degree of hydrolysis of not less than 98 mol % and an average polymerization degree of not less than 1,000 into a mold, followed by freezing and thawing of the thus cast mass. The phantom proposed previously has an advantage that it has a water content and T.sub.1 and T.sub.2 values resembling those of soft living tissues, and it can be used as a material satisfying the aforementioned requirements.
However, the hydrogel having a high water content, as described in the preceding paragraph, is applied for use while being contained in a sealed container made of a plastic material in order to prevent air-drying of the hydrogel. When the hydrogel is used for the inspection of discrimination ability of the system on the samples having different NMR characteristics, plural gel masses which are differentiated in water content (or differentiated in relaxation time by the addition of an agent for shortening the relaxation time) are prepared and placed side by side, and then the image of the boundary region between these gel masses is observed. However, the walls of the sealed containers for respective hydrogel masses appear as dark or black lines in the image. This problem may be avoided by placing the bare hydrogel masses directly side by side and then contained in a sealed container. However, it is inevitable that a gap is left at the boundary region which is imaged as a dark or black line. In addition, water or the agent for shortening the relaxation time tends to migrate through the boundary region (interlaminar transportation). It has been tried to pack hydrogel samples having different NMR characteristics individually in separate containers made of thin plastic films. However, gaps are left at the boundary regions between the adjacent packed hydrogels, and there is another problem that bubbles are formed in the packed hydrogel masses. Although formation of bubbles may be obviated by the use of vacuum packing technique, respective hydrogel masses must be packed in containers which are made of hard and thick plastic films in order that the packed masses retain their shapes and dimensions to avoid gaps formed between the adjacent packed hydrogel masses. Accordingly, the problem of appearance of dark or black lines due to walls of the containers cannot be solved by separate packing of different hydrogel masses.